Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male weanling Fischer 344 rats were fed either a semipurified diet deficient in the methyl donors methionine, choline, and folic acid or a supplemented control diet for a period of 9 weeks. At intervals of 2, 5, and 7 days, 3 weeks, and 9 weeks after initiation of the respective diets, the relative level of DNA strand breaks and the degree of cytosine methylation were quantified in high molecular weight DNA and also within the p53 gene in liver samples from these rats. Genome-wide strand break accumulation was associated with progressive genomic hypomethylation and increased DNA methyltransferase activity. With the use of quantitative PCR as a gene-specific DNA strand break assay, unique DNA strand breaks were detected in exon 5 but not in exons 6-8 of the p53 gene, and were accompanied by significant p53 gene hypomethylation. DNA hypomethylation has been shown to alter the conformation and stability of the chromatin structure, rendering affected regions more accessible to DNA-damaging agents. To determine whether methylation status alters the sensitivity of DNA to strand breakage, DNA in isolated nuclei was methylated in vitro and exposed to endogenous calcium/magnesium-dependent endonuclease activated under defined conditions. The incidence of enzyme-induced DNA strand breaks was decreased significantly with increased DNA methylation. In nuclei isolated from livers of methyl-deficient rats, the hypomethylated DNA was found to be more sensitive to enzyme- and oxidant-induced DNA strand break induction. Taken together, these results provide evidence that DNA strand breaks are induced in high molecular weight DNA and also within the p53 gene in liver tissue from methyl-deficient rats. The increased incidence of these strand breaks in DNA from methyl-deficient rats may be related to alterations in chromatin accessibility associated with DNA hypomethylation.
 ...
PMID:Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. 779 83

WAF1/CIP1, a gene up-regulated by p53 encodes an inhibitor of cyclin-dependent kinases. Induction of WAF1/CIP1 in cells with intact p53 is believed to be instrumental in cell cycle arrest and apoptosis caused by DNA damage. In a model system, WAF1/CIP1 has been shown to have tumor suppressive activity. It is not known however whether WAF1/CIP1 is mutated in human primary tumors. Cells from colorectal cancer have been shown to acquire a series of genetic alterations, including frequent p53 mutations. Thus colorectal tumors, particularly those without identified p53 mutations, are good candidate to search for putative WAF1/CIP1 mutations. DNA extracted from 45 tumors, (including 28 tumors for which p53 mutations had previously been searched for and not found) were PCR amplified for exon 2 of WAF1/CIP1. A search for point mutations was performed in each amplified product using a denaturing gradient gel electrophoresis (DGGE) technique which enables the efficient screening of codons 9 to 139 (i.e. 80% of the WAF1/CIP1 coding sequence). Two different DNA variants were identified and shown to be present in constitutional DNAs of the corresponding patients. The first variant, a C to A transversion at codon 31, changes a serine for an arginine and was detected in eight tumors (18% of the cases). The second variant, detected in a single case (2%) is a silent A to T transversion at the third base of codon 91. DNA extracted from 70 unrelated members from the Centre d'Etude du Polymorphisme Humain (CEPH) was screened for these polymorphisms. The ser/arg polymorphism of codon 31 was detected in seven cases (10%) thus suggesting that it is not associated with a marked colorectal cancer predisposition. The polymorphism on codon 91 was not detected. Two additional variants (arginine to histidine at position 67 and threonine to methionine at position 80) were observed once each in the CEPH family members. Somatic mutation of the WAF1/CIP1 gene was not observed, indicating that, unless there are hot spots for mutations outside the screened region, this gene is not a frequent site of point mutation in colorectal cancer.
 ...
PMID:Polymorphisms and probable lack of mutation in the WAF1-CIP1 gene in colorectal cancer. 784 85

Changes in the pattern of DNA methylation have been a consistent finding in cancer cells. The mostly descriptive nature of these studies and the fact that both hypo- and hypermethylation have been observed at various loci have made it difficult to assess whether these changes are causally involved in the transformation process or whether they reflect the altered physiology of rapidly dividing cancer cells. It is clear, however, that DNA methylation plays an important role in the generation of mutations in human tumors. The high incidence of C-to-T transitions found in the p53 tumor-suppressor gene is attributed to the spontaneous deamination of 5-methylcytosine residues. The multiple observations linking DNA methylation to cancer can be resolved in a model proposing that the high rate of mutation at CpG dinucleotides is due in part to methyltransferase-facilitated deamination. Support for a role of DNA methyltransferase as a mutator enzyme is provided by work with a prokaryotic DNA methyltransferase under S-adenosyl-methionine methyl-donor limiting conditions. Methyl-donor limiting conditions might arise in early stages of tumor development, leading to high rates of methyltransferase-mediated CpG mutagenesis, as seen in human tumors. Such a mechanism is consistent with the frequently reported methionine auxotrophy of cancer cells and with the tumorigenic effects of methyl-deficient diets. Methyl deficiency in tumor cells is also consistent with the commonly observed global hypomethylation of tumor cell DNA, despite normal or even high levels of DNA methyltransferase expression.
 ...
PMID:DNA methylation and cancer. 784 43

Chemotaxis and motility of B. sphaericus 2362 were monitored as the function of a batch culture age. It was found that both functions changed independently during growth of the culture. Motility was low until the late logarithmic stage ensued, whereafter it increased sharply. The ability of cells to respond to chemoeffectors peaked at the mid-logarithmic phase. A major methyl-accepting chemotaxis protein (P53, M(r) = 53 kDa) was identified. The extent of label incorporation in this protein from L-[methyl-3H]methionine was maximal in mid- and late logarithmic phases of the growth. Cells in stationary cultures incorporated very low amounts of the label. At any stage, the labeling was maximal in starved cells; it was almost abolished in cells pre-incubated with amino acids. Although extents of P53 labeling in mid- and late logarithmic cells were similar, late logarithmic cells demonstrated a considerably impaired chemotaxis. Supermotile sporulating cells were practically insensitive to environmental stimuli. The difference in development of sensory and locomotive functions may be interpreted as an adaptive response. A well developed sensory apparatus would allow vegetative cells to adapt efficiently to fluctuating attractant gradients. Insensitive sporulating cells would tend to disperse randomly from the nutrient-exhausted area. Thus, spore formation would occur in larger volume of the habitat, increasing the chance of the microbial population to survive.
 ...
PMID:Motility and chemotaxis in Bacillus sphaericus. Dependence upon stage of growth. 798 66

Exposure of mammalian cells to UV radiation and other DNA-damaging agents triggers a response known as the UV response. This induction response involves a large number of genes including c-jun, cell-cycle regulatory proteins, specific repair enzymes, and the tumor suppressor gene p53. Altered expression of these genes following DNA damage is hypothesized to result in G1 arrest, thereby allowing cells to repair DNA damage prior to cell division. In the present study, we investigated expression of the p53 gene in mouse keratinocyte cell line 308 after exposure to UV-B light at a biologically relevant dose. Irradiation of 308 cells with 40 J/m2 UV-B resulted in a 4- to 10-fold induction in the level of p53 protein, peaking at 5 h post-irradiation. Northern blot analysis of RNA from UV-B irradiated cells showed no change in the steady-state level of p53 mRNA following irradiation. However, the half-life of p53 protein in UV-B irradiated 308 cells was extended approximately 7-fold, from 30 to 200 min. Additional studies were performed with specific anti-p53 monoclonal antibodies to establish whether UV-B irradiation induced a conformational change in p53 protein in irradiated cells. Metabolic labeling with 35S-methionine followed by immunoprecipitation with p53 monoclonal antibody PAb246, which recognizes the wild-type murine p53 protein, demonstrated that the p53 protein present in 308 cells possessed the wild-type conformation both before and after UV-B irradiation. In contrast, p53 antibody PAb240, which recognizes a 'conformation-dependent' epitope, was not reactive with the p53 protein present in 308 cells. Therefore, we conclude that the induction of p53 protein in mouse keratinocytes following UV-B irradiation occurred posttranscriptionally, and was due to a significant increase in p53 protein half-life.
 ...
PMID:Increase in p53 protein half-life in mouse keratinocytes following UV-B irradiation. 802 Jan 38

Chemotaxis and motility of Bacillus sphaericus 2362 were monitored as a function of the batch culture age. It was found that both functions changed independently during growth of the culture. Motility was low until the late logarithmic stage ensued, whereafter it increased sharply. The ability of cells to respond to chemo-effectors peaked at the mid-logarithmic phase. A major methyl-accepting chemotaxis protein (P53, M(r) = 53 kDa) was identified. The extent of label incorporation in this protein from L-[methyl-3H]methionine was maximal in mid- and late-logarithmic phases of the growth. Cells in stationary cultures incorporated very low amounts of the label. At any stage, the labeling was maximal in starved cells; it was almost abolished in cells pre-incubated with amino acids. Although extents of P53 labeling in mid- and late logarithmic cells were similar, late logarithmic cells demonstrated a considerably impaired chemotaxis. Supermotile sporulating cells were practically insensitive to environmental stimuli. The difference in development of sensory and locomotive functions may be interpreted as an adaptive response. A well developed sensory apparatus would allow vegetative cells to adapt efficiently to fluctuating attractant gradients. Insensitive sporulating cells would tend to disperse randomly from the nutrient-exhausted area. Thus, spore formation would occur in larger volume of the habitat, increasing the chance of microbial population to survive.
 ...
PMID:Motility and chemotaxis in Bacillus sphaericus. Dependence upon stage of growth. 803 8

Two main histological variants of gastric carcinoma have been identified: intestinal and diffuse types. The former is preceded by a sequential chain of events characterized as chronic gastritis, atrophy, intestinal metaplasia, dysplasia, intramucosal carcinoma, and invasive neoplasia. The second type (diffuse) lacks well-recognized precursor changes. Genotypic events in the gastric precancerous process are described, but a clear model of their sequence and relevance is lacking. Cadherins may play a role in determining which type of carcinoma develops. Translocated promoter region-MET rearrangements have been identified since early stages of the process. p53 alterations are reported beginning with the dysplasia stage utilizing immunohistochemical techniques. Single-strand conformation polymorphism and sequencing analysis show alterations in early stages, especially G:C to A:T transitions.
 ...
PMID:Phenotypic and genotypic events in gastric carcinogenesis. 813 16

From an hepatocarcinoma cell line (LFCL.2A), unable to grow in a culture medium in which methionine was replaced by L-homocysteine, we had previously isolated revertant clones presenting a low growth rate, a loss of tumorigenicity and an inhibition of transcription of three oncogenes: c-Ki-ras, c-Ha-ras and c-myc. Here we showed that long-term deprivation of methionine led to a depletion of spermine, while putrescine and spermidine contents remained unchanged. When the revertant cells were shifted in a medium containing methionine, the oncogene transcription (except the p53 gene) started very rapidly in parallel with an increase in the putrescine content. By contrast, spermidine and spermine contents decreased during the first hours but were not significantly different from control values after numerous subcultures in methionine-containing medium.
 ...
PMID:Polyamine content and oncogene expression in hepatoma cells in culture during methionine deprivation and refeeding. 839 Aug 3

The p53 gene was examined in a series of formalin-fixed paraffin-embedded astrocytic neoplasms of various types by polymerase chain reaction (PCR), single-strand conformation polymorphism analysis (SSCP), and direct sequencing of amplified DNA. PCR primers were designed to amplify three DNA fragments encompassing exons 5, 7, and 8 with splice sites, including all four mutational "hot spots" within this gene. SSCP was performed in a polyacrylamide gel containing 10% glycerol. Two mutations were found among the 20 high and intermediate grade adult astrocytomas studied by this sensitive screening technique and confirmed by sequencing of the PCR product. (1) An anaplastic astrocytoma disclosed a T-A transversion in Codon 246 giving rise to a methionine to lysine amino acid substitution. (2) A giant cell glioblastoma disclosed a G to A transition in Codon 285 resulting in a glutamic acid to lysine substitution. Both mutations were associated with loss of the normal allele. Twenty-three DNA fragments that disclosed no mutation by SSCP analysis were confirmed to be negative by direct sequencing of amplified DNA. No mutations were detected in a series of eight juvenile cerebellar astrocytomas, a biologically distinct form of low-grade astrocytoma. Mutations of the p53 gene may play an important pathogenetic role in a subset of human astrocytomas.
 ...
PMID:Mutations in the p53 gene in human astrocytomas: detection by single-strand conformation polymorphism analysis and direct DNA sequencing. 841 89

Hepatocyte growth factor/scatter factor (HGF/SF) can elicit a wide variety of effects upon cells expressing its receptor, the tyrosine kinase proto-oncogene product Met, including mitogenicity, motility, and morphogenesis. Normally, met expression is restricted to epithelial cells and is activated in a paracrine fashion by HGF/SF secreted from cells of mesenchymal origin. In this chapter, we review data showing that: (i) met over-expression in HGF/SF-expressing NIH/3T3 fibroblasts leads to sarcomagenesis and metastasis via an autocrine mechanism; (ii) Met-HGF/SF autocrine signalling occurs to a low level in normal fibroblasts and to a much greater extent in human sarcomas and sarcoma cell lines; (iii) met expression is enhanced as p53-deficient fibroblasts are passaged in vitro and (iv) met and HGF/SF over-expression are selected for during tumorigenesis of p53-deficient late-passage fibroblasts. Thus, loss of p53 predisposes a mesenchymal cell to over-express met and high level Met-HGF/SF autocrine signaling in mesenchymal cells promotes both sarcomagenesis and metastasis through inappropriate induction of the pleiotropic responses to Met-HGF/SF stimulation.
 ...
PMID:The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis. 852 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>